Defensive responses to danger are essential to survival and are seen throughout the animal kingdom, including in humans. In rodents, predator odors stimulate instinctive fear responses that include characteristic behaviors and increases in blood levels of stress hormones. The stress hormone response to predator odors and other stressors results from activation of the HPA (hypothalamic-pituitary-adrenal) axis, which involves a subset of corticotropin releasing hormone (CRH) neurons in the hypothalamus. In humans, as in rodents, stressful stimuli increase blood levels of stress hormones, suggesting the evolutionary conservation of mechanisms underlying physiological responses to fear and stress. Dysregulation of the HPA axis is seen in certain human psychiatric conditions, further suggesting that an understanding of the neural mechanisms that control stress hormones in rodents might ultimately provide insights relevant to human disease. The stereotyped nature of fear responses to predator odors in mice suggests the existence of genetically determined neural circuits that include olfactory receptors (ORs) in the nose that selectively detect those odors and specific subsets of brain neurons that receive signals from those receptors and generate their profound downstream effects on physiology and behavior. To gain insight into the molecular mechanisms and neural circuits that underlie stress hormone responses to predator odors, we propose to employ a combination of tools, including neural circuit tracing with neurotropic viruses that travel across one or multiple synapses, next generation RNA sequencing (RNA-Seq), high throughput screening, analyses of neural activity markers, and pharmacogenetic manipulation to activate or silence specific subsets of neurons. Using these tools, we will identify receptors in the nose that transmit signals to CRH neurons, identify odor molecules detected by those receptors, and determine whether the individual odor molecules stimulate stress hormone increases that mimic fear or instead block stress hormone increases, as it now appears some odors can do. To determine how the receptor signals are translated into specific responses by the brain, we will test the hypothesis that this is accomplished via the actions of specific subsets of neurons in the olfactory cortex and by selected non- olfactory brain areas that relay fear signals from the olfactory cortex to CRH neurons. To do this, we will investigate the locations of neurons in the olfactory cortex and other brain areas that are activated by predator odors and have the ability to transmit signals to CRH neurons. By activating and inhibiting neurons in specific areas, it will be possible to assess whether individual areas can either induce or suppress fear and whether those areas are required for the transmission of excitatory or inhibitory signals to CRH neurons that affect stress hormones. Together, these studies should provide significant insights into the molecular mechanisms and neural circuits that govern the profound impact of fear and stress-inducing odor stimuli on physiology.